|3d1v, resolution 2.70Å ()|
|Gene:||NP, PNP (Homo sapiens)|
Crystal structure of human PNP complexed with 2-mercapto(3H) quinazolinone
Human purine nucleoside phosphorylase (HsPNP) is a target for inhibitor development aiming at T-cell immune response modulation. In this work, we report the development of a new set of empirical scoring functions and its application to evaluate binding affinities and docking results. To test these new functions, we solved the structure of HsPNP and 2-mercapto-4(3H)-quinazolinone (HsPNP:MQU) binary complex at 2.7A resolution using synchrotron radiation, and used these functions to predict ligand position obtained in docking simulations. We also employed molecular dynamics simulations to analyze HsPNP in two conditions, as apoenzyme and in the binary complex form, in order to assess the structural features responsible for stability. Analysis of the structural differences between systems provides explanation for inhibitor binding. The use of these scoring functions to evaluate binding affinities and molecular docking results may be used to guide future efforts on virtual screening focused on HsPNP.
Structural studies of human purine nucleoside phosphorylase: towards a new specific empirical scoring function., Timmers LF, Caceres RA, Vivan AL, Gava LM, Dias R, Ducati RG, Basso LA, Santos DS, de Azevedo WF Jr, Arch Biochem Biophys. 2008 Nov 1;479(1):28-38. Epub 2008 Aug 30. PMID:18790691
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[PNPH_HUMAN] Defects in PNP are the cause of purine nucleoside phosphorylase deficiency (PNPD) [MIM:613179]. It leads to a severe T-cell immunodeficiency with neurologic disorder in children.
[PNPH_HUMAN] The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.
About this Structure
- Timmers LF, Caceres RA, Vivan AL, Gava LM, Dias R, Ducati RG, Basso LA, Santos DS, de Azevedo WF Jr. Structural studies of human purine nucleoside phosphorylase: towards a new specific empirical scoring function. Arch Biochem Biophys. 2008 Nov 1;479(1):28-38. Epub 2008 Aug 30. PMID:18790691 doi:10.1016/j.abb.2008.08.015
- de Azevedo WF Jr, Canduri F, dos Santos DM, Silva RG, de Oliveira JS, de Carvalho LP, Basso LA, Mendes MA, Palma MS, Santos DS. Crystal structure of human purine nucleoside phosphorylase at 2.3A resolution. Biochem Biophys Res Commun. 2003 Aug 29;308(3):545-52. PMID:12914785
- ↑ Williams SR, Gekeler V, McIvor RS, Martin DW Jr. A human purine nucleoside phosphorylase deficiency caused by a single base change. J Biol Chem. 1987 Feb 15;262(5):2332-8. PMID:3029074
- ↑ Aust MR, Andrews LG, Barrett MJ, Norby-Slycord CJ, Markert ML. Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency. Am J Hum Genet. 1992 Oct;51(4):763-72. PMID:1384322
- ↑ Pannicke U, Tuchschmid P, Friedrich W, Bartram CR, Schwarz K. Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient. Hum Genet. 1996 Dec;98(6):706-9. PMID:8931706
- ↑ Ealick SE, Rule SA, Carter DC, Greenhough TJ, Babu YS, Cook WJ, Habash J, Helliwell JR, Stoeckler JD, Parks RE Jr, et al.. Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution. J Biol Chem. 1990 Jan 25;265(3):1812-20. PMID:2104852